Cl− channels and proposed functions in vascular smooth muscle cells

Cl− channels and proposed functions in vascular smooth muscle cells. Cl− channels and their corresponding molecular candidate genes and cellular functions are indicated. CFTR, cystic fibrosis transmembrane conductance regulator, encodes Cl− channels activated by stimulation of cAMP-protein kinase A (PKA) pathway (ICl, PKA), protein kinase C (PKC) (ICl, PKC), or extracellular ATP through purinergic receptors (ICl, ATP). CFTR is composed by two membrane spanning domains (MSD1 and MSD2), two nucleotide binding domains (NBD1 and NBD2) and a regulatory subunit (R). Gi, heterodimeric inhibitory G protein; A1R, adenosine type 1 receptor; AC, adenylyl cyclase; H2R, histamine type II receptor; Gs, heterodimeric stimulatory G protein; α-AR, α-adrenergic receptor; β-AR, β-adrenergic receptor; P2R, purinergic type 2 receptor; P, phosphorylation sites for PKA and PKC; PP, serine-threonine protein phosphatases. ICl, Ca is a Cl− current activated by increased intracellular Ca2+ concentration ([Ca2+]i); Molecular candidates for ICl, Ca include TMEM16A (transmembrane protein 16A), the Bestrophin gene family and CLCA1, a member of a Ca2+-sensitive Cl− channel family (CLCA). CLC-3, a member of voltage-gated CLC Cl− channel family, encodes Cl− channels that are volume-regulated (ICl, vol) and can be activated by cell swelling (ICl, swell) induced by exposure to hypotonic extracellular solutions or possibly membrane stretch. ICl, b is a basally-activated CLC-3 Cl− current. Membrane topology model (α-helices a-r) for CLC-3 is modified from Dutzler et alCLC-3 proteins are expressed on both sarcolemmal membrane and intracellular organelles including mitochondria (mito) and endosomes. The proposed model of endosome ion flux and function of Nox1 and CLC-3 in the signaling endosome is adapted from Miller Jr et al. Binding of IL-1β or TNF-α to the cell membrane initiates endocytosis and formation of an early endosome (EEA1 and Rab5), which also contains NADPH oxidase subunits Nox1 and p22phox, in addition to CLC-3. Nox1 is electrogenic, moving electrons from intracellular NADPH through a redox chain within the enzyme into the endosome to reduce oxygen to superoxide. CLC-3 functions as a chloride–proton exchanger, required for charge neutralization of the electron flow generated by Nox1. The ROS generated by Nox1 result in NF-κB activation. Both CLC-3 and Nox1 are necessary for generation of endosomal ROS and subsequent NF-κB activation by IL-1β or TNF-α in VSMCs. Statins block CLC-3 channels, which causes hyperpolarization of the cell membrane, closure of Ca2+ channels and vasorelaxation, and inhibition of cell proliferation. Nox: NADPH oxidase.

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Chloride channels in stroke. (2013) Ya-ping Zhang, et al. Acta Pharmacol Sin. 2013 Jan;34(1):17-23. Figure: F1. All organisms Mus musculus Homo sapiens Rattus norvegicus Bos taurus Xenopus laevis Drosophila melanogaster

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